Nicotinic acid ester of certain hydroxyalkyleneimino-diacetamides



Unite States Home Products Corporation, New York, N.Y., a cor poration of Delaware No Drawing. Filed Aug. 7, 1958, Ser. No. 753,634 2JClaims. omen-495.5

This invention relates to chemical; compounds of the atent amide type and, more particularly, to carbalkoxyamino di-fatty acid amides, their salts, and methods. for producing them. This application isv a continuation-impart of application Ser. No. 629,444,. filed December 20,. 1956, now abandoned, which, in turn, was a division of application Serial No. 495,038, filedMarch 17, 1955, now Patent The. compounds of-the invention, in the form of the free bases,,-may be represented by the formula: 1

, Ra. cm-co-N RI ore-o ON/ radicals, The aralkyl radicals R and R, may represent phenylor substituted phenyl-lower alkylradicals wherein such substituents as. lower alkyl, lower alkoxy liydroxy, Halogen, nitro,, amino, monoor di-lower alkylammo radicals may be on the ring. In the case of aralkyls of the p-phenylethyl type, hydroxy substituents on the 5-- carbon of'tlie alkyl are also contemplated; With regard to R the lower alkylene portion of the radical should have from-2 to 4 carbon atoms:

The present invention deals specifically with nicotinic and benzoic acid esters and the R heterocyclic or aromatic ring may either be substituted or unsubstituted. If substituted, such substituents as lower alkyl, lower alkoxy, benzyl ether, hydroxy, halogen, nitro, amino, monoor di-lower alkyl amino groups may be present to the extent of one to three substituents on the ring.

It has been discovered that compounds meeting the described qualifications, whether as the free base or the acidaddition salts, possess pharmacological activity and particularly surprisingly good local anesthetic action. The latter action has been noted when R represents a hydroxy-lower alkyl or the above-mentioned esters of the hydroxy-lower alkyls. The replacement of the hydroxy group with an amino radical, for example, destroys the local anesthetic action as found in testing the compound Additionally, where R involves a straight-chain alkylene group of more than 4 carbon atoms, no local anesthetic action could be found as discovered in testing From: the accumulated evidence, it therefore appears thatthe local anesthetic action is selective for certain compounds: and, further, that noprediction with regard to local anesthetic action is possible where R5 represents other radicals.

Compounds falling within the scope of the formula as given: above. may be used in the form of their acid-addition salts while still retaining? their effectiveness for local anesthetic use. The salts provide great flexibility in therapeutic use since they may impart various degrees of watersolubility toan otherwise substantially insoluble base. With regard to the acid-addition salts, either organic or inorganic acids may be used aslong as they do not sub-- stantially increase the toxicity of the compound. Among the salts considered useful for the purposes indicated are the hydrochloride, sulfate, phosphate, hydrobromide, ace tate, tartrate, propionate or succinate.

Inpreparing the di-fatty. acid amides, where the amides are similar, the free bases are prepared by reacting. a

lower alkanolamine with an alpha-halo-fatty acid amide ina molar ratio of 1 :22, but preferably'the latter being pres ent in slight excess of this ratio; On the other hand; where the fatty acid amides are dissimilar, .asyfor' example, Where R diifers from R or where R, diflers from R the'bases are prepared byreacting an alkanolamiiio fatty acid amide with a halo-fatty acid amide in a molar ratio of about 1:1. The halogen atom may be either chlorine or bromine. The alkanolamine-fattyacid amide is prepared as taught" by the general procedure outlined in the patents to Bruce et a1. 2,568,142, dated September 18, 1951, or2,654,754, dated October 6, 1953, suitably modified, of course, to provide'the proper a'mineand halo genated reactants.

The reaction of the alkanolamine or alkanolaminofatty acid amide and halo-fatty acid amide is carried out substantially under the conditions as described in the above-mentioned patents. The reaction temperature is in the range of about to abouti200 C. but is preferably in the narrower range of about" to about 180 C. Alcohols of 3 to 7 carbon'atoms, anisole, dioxane, hydrocarbon solvents, such as xylene, or, in fact, any inert solvent boiling within the ranges indicated are suitable, the reaction taking place at the refluxing temperature of the solvent. Acid acceptors or mildly basic material are also provided for the reaction, these acceptors being, for example, pyridine, an alkali or alkaline earth metal oxide, carbonate or bicarbonate or like substances.

The esters are easily formed from the alkanol compounds by known procedures. Typical methods involve reacting the alkanol di-fatty acid amide with an acid, acid anhydride, acid or acyl halide, with the anhydride and halide being preferred. The reaction is carried out in a suitable inert solvent, such as hydrocarbon or chlorinated hydrocarbons, typical examples being benzene, toluene, chloroform and dichloromethane. An alkaline material may be provided as an acid acceptor for the reaction, if necessary, this being either alkaline metal hydroxide or carbonate or a tertiary amine. The temperature for esterification depends on thereactants and may range from about 0 to about C.

The salts may be prepared in any manner known to erally dissolves the free base in a suitable solvent and adds the selected acid thereto. The preparation of acid here.

The following examples illustrate the preparation of typical compounds falling within the scope of the invention. I-.. I I. r

"f f EXAMPLE L T Preparation of: N,N-di-(N-methyl-N-omega-phenyl-tert.

butylacetamido)-beta-aminoethyl nicotinate and salt thereof 7 "I l Two grams (0.004 mole) N,N-di-(N-methyl-N-omegaphenyl-tert.butyl-acetamido)beta-hydroxyethylamine was dissolved in 50 cc. dry benzene. 0.9 gram (0.004-mole) nicotinic acid anhydridewas added and the reaction refluxed 16 hours. The reaction mixture was 'cooled' and nicotinic acid (M.Pl 234-235 C.) was filtered ofi. The filtrate was concentrated under vacuum to syrup. This was taken up'in acetone and refiltered. The filtrate was treated with dry hydrogen chloride. The precipitate was filtered, washed with acetone and'dried: M.P.': 158'- 159 C.

' ANALYSIS Fnd .4. Q

ll. 33 Chi! ll. 35

do)amino-isopropanol (1.2 grams, 0.002 mole) and nicotinic acid anhydride (0.5' gram, 0.002 mole) in 50 cc. anhydrous benzene was refluxed'16 hours; Aftercooling the reaction mixture was washed twice with a saturated aqueous solution of sodium carbonate, then three times with water. The benzene layer was dried over magnesium sulfateand filtered; the filtrate was then concentrated to a syrup. .The free base'wasdissolved in acetone-ether 1/1) and precipitated 'with dry hydrogen chloride as the hydrochloride salt. Recrystallization from acetone-methanol'yieldedthe product as hydrochloride-dihydrate. M.

. ANALYSIS 7 o H N o1 H20 (K. Fisher) Fnd 60.84 710 8.08 1 10.61 4.86 Oalc 60.40 156 7.48 10.22 5.18

magnesium sulfate. The oily residue was washed by trituration'with hexane EXAMPLE 3 Preparation of: 'y-N,N-di(N-methyl hfibenzyl-acelamz'do) aminopropyl nicotinate and salt thereof To a refluxing solution of 2.2 grams (0.01 mole) nicotinic acid anhydride in.l00 cc. .dry benzene was added 4 grams (0.01 mole) N,N-di-(N-methyl-N-benzyl-acetamido)aminopropanol; Refluxed, 16. hours, cooled and removed nicotinic acid by filtration. The filtrate con centrated toa syrup. The basewas redissolved in etheracetone"( 1/ 1), and treated with a slight excess of dry hydrogen chloride. This oil, after decanting oif solvent was dissolved in a small amount of water and obtained as f a hydroscopic powder.

EXAMPLE 4 To as grams 0.02 men N,N-di-(N-methyl-N-[phenyl-Jisopropyl acetamido) aminoethanol in cc. drytoluene was added one drop 50% sodium dispersion and the reaction refluxed. Ethyl nicotinate, 3 grams (0.02 mole), was added and, refluxing continued 3 hours. About 20 'cc. toluene distilled ofi slowly under slight vacuum. After cooling the solution was washed with water, dried over Toluene removed under vacuum.

twice. A portion of the oil base in either was converted to a hydroscopic hydrochloride which was vacuum dried.

We claim: 1. A compound of the group consisiting of di-fatty acid amides and the non-toxic acid-addition salts thereof, said amides having the general formula CHFC 0N R: CH3OON R4 wherein R and R represent lower alkyl radicals, R and R stand for phenyl-lower alkyl radicals and the term alk represents a divalent alkylene radical having from 2 to 4 carbon atoms.

2. The compound, N,N-di(N methyl-N-omega-phenyl- -tert.butyl-acetamido)-fl-aminoethyl nicotinate.

References Cited in the file of this patent UNITED STATES PATENTS 2,780,64d Seifter et al Feb. 5, 1951 

1. A COMPOUND OF THE GROUP CONSISTING OF DI-FATTY ACID AMIDES AND THE NON-TOXIC ACID-ADDITION SALTS THEREOF, SAID AMIDES HAVING THE GENERAL FORMULA WHEREIN R1 AND R3 REPRESENT LOWER ALKYL RADICALS, R2 AND R4 STAND FOR PHENYL-LOWER ALKYL RADICALS AND THE TERM "ALK" REPRESENTS A DIVALENT ALKYLENE RADICAL HAVING FROM 2 TO 4 CARBON ATOMS. 